Hypothyroidism In Cancer Patients Research Articles

Tyrosine kinase inhibitor-induced hypothyroidism: mechanism and clinical implications.

Since the first experimentally proven tyrosine kinase inhibitor (TKI) imatinib was introduced in the clinical setting, TKIs have attracted widespread attention because of their remarkable therapeutic effects and improvement of survival rates. TKIs are small-molecule, multi-target, anti-cancer agents that target different tyrosine kinases and block downstream signaling. However, with in-depth research on TKI drugs, the adverse reactions-for example, thyroid dysfunction-have become a concern and thus have attracted the attention of numerous researchers. Thyroid dysfunction, especially hypothyroidism, that occurs in high incidence during TKI therapy has a close relationship with treatment efficacy, but the mechanism of TKI-induced thyroid dysfunction is obscure. This review discusses the epidemiology, possible mechanisms, and clinical significance of hypothyroidism in cancer patients treated with TKI.

An Analytical Study to Determine Dose-Volume Threshold for Radiation Induced Hypothyroidism.

Objective: To determine radiation dose volume threshold in predicting the development of hypothyroidism in cancer patients following neck irradiation. Methods: This is a cross sectional follow up study for patients who had been previously irradiated, prior to enrolment in the study. We have done thyroid dose-volumetric analysis on 120 histologically proven cancer patients in the age group of 18-75 years who received neck irradiation as a part of their definitive or adjuvant radiotherapy with three-dimensional conformal or intensity-modulated radiotherapy technique (3D -CRT or IMRT) and completed at least six months post-radiotherapy. Primary tumor sites included carcinoma or lymphoma of the head and neck, breast, cervical, and upper thoracic esophagus, requiring neck irradiation. Results: The proportion of patients who tested positive for Radiation induced hypothyroidism (RIHT) was found to be 40%, with clinical hypothyroidism and subclinical hypothyroidism being 25.8% and 14.2%, respectively. Time to develop hypothyroidism peaks around two years. Mean thyroid gland dose (Dmean) >28 Gy, thyroid gland volume receiving 40 Gy dose (i.e. V40) >49% and age <50 years were found to be significant risk factors for the development of RIHT on binary logistic regression. RT dose >50 Gy and thyroid gland volume spared from 40 Gy (i.e. VS40) < 2.12cm3 were statistically significant predictors for RIHT on chi-square and (Receiver operating characteristic) ROC curve analysis respectively but not on regression analysis. Conclusion: Dose-volume threshold for the thyroid gland as Dmean <28 Gy and V40 <49% may prevent the development of RIHT.

1771P - Hypothyroidism in cancer patients received multikinase inhibitors: Risk factors and outcomes

Background: Hypothyroidism was a known and common side effect from multikinase inhibitors notably in sunitinib, pazopanib and sorafenib. The goal of this study was to explore risk factors in developing hypothyroid and whether the occurrence of this endocrine adverse event (AE) leading to better survival outcomes. Methods: Seventy-one renal cell carcinoma (RCC) patients and 136 hepatocellular carcinoma (HCC) patients were retrospectively analyzed. Data relating to the treatment course and development of hypothyroid were collected, extracted and presented in separate cohort. Results: The incidence of hypothyroidism was 47.8% in RCC patients treated with either sunitinib or pazopanib. For HCC patients whom received sorafenib, the incidence of hypothyroidism was 31.8%. We found no factor significantly associated with hypothyroidism in RCC patients. HCC patients whom had duration of treatment of less than 3 months tend to develop hypothyroidism. There was no significant association between the development of hypothyroid and PFS or OS in RCC patients. In HCC group, euthyroid patients had statistically significant longer mPFS [7.6 vs. 2.2 months; HR = 6.38; 95%CI 1.87-21.8; p = 0.003] and mOS (16.9 vs. 5.2 months; HR = 22.96; 95%CI 4.45-118; p = 0.<001) than the hypothyroid group. Conclusions: Hypothyroid is the most common endocrine AE of multikinase inhibitors. There are no significant clinical factors associated with the development of hypothyroid. This AE might serve as a good predictive marker for multikinase inhibitors treatment in HCC patients and their survival outcomes. The larger cohort is needed to confirm this evidence. Legal entity responsible for the study: Faculty of Medicine Ramathibodi Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers.

Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction is recognized as a common adverse effect of treatment, but the importance of incident hypothyroidism during TKI therapy remains unclear. This study analyzed the prognostic significance of hypothyroidism during TKI therapy in cancer patients. This was a retrospective cohort study of adult patients with advanced nonthyroidal cancer treated with TKI and available thyroid function testing at three affiliated academic hospitals from 2000 to 2017. Patients with preexisting thyroid disease were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid status with TKI treatment was determined from thyroid function testing and initiation of thyroid medication, and classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH >10 mIU/L, low free thyroxine, or requiring replacement). Multivariate models were used to evaluate the effect of TKI-related hypothyroidism on overall survival (OS). Of 1120 initial patients, 538 remained after exclusion criteria. SCH occurred in 72 (13%) and OH in 144 (27%) patients with TKI therapy. Patients with hypothyroidism had significantly longer OS, with median OS in euthyroid patients of 685 days [confidence interval (CI) 523-851] compared to 1005 days [CI 634-1528] in SCH and 1643 days [CI 1215-1991] in OH patients (p < 0.0001). After adjustment for age, sex, race/ethnicity, cancer type, cancer stage, ECOG performance status, and checkpoint inhibitor therapy, OH remained significantly associated with OS (hazard ratio = 0.561; p < 0.0001), whereas SCH did not (hazard ratio = 0.796; p = 0.165). Analysis of hypothyroid patients (SCH and OH) with TSH >5 and <10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement. New hypothyroidism in cancer patients treated with TKI is associated with significantly improved OS, should not necessitate TKI dose reduction or discontinuation, and may provide independent prognostic information.

1437PD - Pooled analysis of treatment-related hypothyroidism with anti-PD-1/PD-L1 therapies in cancer patients

BackgroundBlockade of programmed death 1 (PD-1), or its ligand, PD-L1, could restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated promising efficacy in the treatment of cancer patients. The toxicity spectrum of PD-1/PD-L1 blockers is distinct from chemotherapy or other target agents. This study aims to investigate the overall incidence of treatment-related hypothyroidism with anti-PD-1/PD-L1 therapies in cancer patients.MethodsA systematic search of literature up to January 2016 was performed in EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using Comprehensive Meta-analysis using fixed or random effects model depending the heterogeneity of the included studies.ResultsA total of 23 clinical trials with 5290 patients were included. The overall incidence of all- and high-grade hypothyroidism in cancer patients receiving anti-PD-1/PD-L1 therapies were 7.3% (95% CI, 5.9% to 9.1%) and 0.4% (95% CI, 0.2% to 0.7%), respectively. Adding anti-CTLA-4 antibodies to PD-1/PD-L1 blockers led to increased incidence of all-grade fatigue (16.4% vs. 6.4%, p < 0.001), but not high-grade fatigue (0.3% vs. 0.4%). When stratified by cancer type, trial phase, drug category or drug dosage, no notably differences in the incidence of hypothyroidism were seen.ConclusionsHypothyroidism is commonly seen with anti-PD-1/PD-L1 therapies in cancer patients. Early and appropriate management is required to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations.Legal entity responsible for the study: Sun Yat-sen University Cancer CenterFundingNational Natural Science Funds of China (Grant No: 81372502)DisclosureAll authors have declared no conflicts of interest. BackgroundBlockade of programmed death 1 (PD-1), or its ligand, PD-L1, could restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated promising efficacy in the treatment of cancer patients. The toxicity spectrum of PD-1/PD-L1 blockers is distinct from chemotherapy or other target agents. This study aims to investigate the overall incidence of treatment-related hypothyroidism with anti-PD-1/PD-L1 therapies in cancer patients. Blockade of programmed death 1 (PD-1), or its ligand, PD-L1, could restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated promising efficacy in the treatment of cancer patients. The toxicity spectrum of PD-1/PD-L1 blockers is distinct from chemotherapy or other target agents. This study aims to investigate the overall incidence of treatment-related hypothyroidism with anti-PD-1/PD-L1 therapies in cancer patients. MethodsA systematic search of literature up to January 2016 was performed in EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using Comprehensive Meta-analysis using fixed or random effects model depending the heterogeneity of the included studies. A systematic search of literature up to January 2016 was performed in EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using Comprehensive Meta-analysis using fixed or random effects model depending the heterogeneity of the included studies. ResultsA total of 23 clinical trials with 5290 patients were included. The overall incidence of all- and high-grade hypothyroidism in cancer patients receiving anti-PD-1/PD-L1 therapies were 7.3% (95% CI, 5.9% to 9.1%) and 0.4% (95% CI, 0.2% to 0.7%), respectively. Adding anti-CTLA-4 antibodies to PD-1/PD-L1 blockers led to increased incidence of all-grade fatigue (16.4% vs. 6.4%, p < 0.001), but not high-grade fatigue (0.3% vs. 0.4%). When stratified by cancer type, trial phase, drug category or drug dosage, no notably differences in the incidence of hypothyroidism were seen. A total of 23 clinical trials with 5290 patients were included. The overall incidence of all- and high-grade hypothyroidism in cancer patients receiving anti-PD-1/PD-L1 therapies were 7.3% (95% CI, 5.9% to 9.1%) and 0.4% (95% CI, 0.2% to 0.7%), respectively. Adding anti-CTLA-4 antibodies to PD-1/PD-L1 blockers led to increased incidence of all-grade fatigue (16.4% vs. 6.4%, p < 0.001), but not high-grade fatigue (0.3% vs. 0.4%). When stratified by cancer type, trial phase, drug category or drug dosage, no notably differences in the incidence of hypothyroidism were seen. ConclusionsHypothyroidism is commonly seen with anti-PD-1/PD-L1 therapies in cancer patients. Early and appropriate management is required to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations.Legal entity responsible for the study: Sun Yat-sen University Cancer Center Hypothyroidism is commonly seen with anti-PD-1/PD-L1 therapies in cancer patients. Early and appropriate management is required to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations.

Hypothyroidism after a cancer diagnosis: etiology, diagnosis, complications, and management.

Hypothyroidism is a common disease that is easily treated in the majority of cases, when readily diagnosed; however, presentation of an aggregate of its symptoms is often clinically overlooked or attributed to another disease and can potentially be lethal. Already prevalent in older women, its occurrence in younger patients is rising as a result of radiation therapy, radioactive iodine therapy, and newer antineoplastic agents used to manage various malignancies. The presence of nonspecific constitutional symptoms and neuropsychiatric complaints in cancer patients can be attributed to a myriad of other diagnoses and therapies. Thyroid dysfunction can be easily overlooked in cancer patients because of the complexity of cancer's clinical picture, particularly in the pediatric population. Underdiagnosis can have important consequences for the management of both hypothyroidism and the malignancy. At minimum, quality of life is adversely affected. Untreated hypothyroidism can lead to heart failure, psychosis, and coma and can reduce the effectiveness of potentially life-saving cancer therapies, whereas iatrogenic causes can provoke atrial fibrillation and osteoporosis. Consequently, the diagnosis and treatment of hypothyroidism in cancer patients are pertinent. We summarize the history, epidemiology, pathophysiology, clinical diagnosis, and management of hypothyroidism in cancer patients.